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Molecular and Cellular Biology, May 2003, p. 3287-3304, Vol. 23, No. 9
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.9.3287-3304.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Regulation of E2F1 by BRCT Domain-Containing Protein TopBP1

Kang Liu,1 Fang-Tsyr Lin,2 J. Michael Ruppert,1 and Weei-Chin Lin1,2*

Division of Hematology and Oncology, Department of Medicine,1 Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294-33002

Received 3 December 2002/ Returned for modification 28 January 2003/ Accepted 7 February 2003

The E2F transcription factor integrates cellular signals and coordinates cell cycle progression. Our prior studies demonstrated selective induction and stabilization of E2F1 through ATM-dependent phosphorylation in response to DNA damage. Here we report that DNA topoisomerase IIß binding protein 1 (TopBP1) regulates E2F1 during DNA damage. TopBP1 contains eight BRCT (BRCA1 carboxyl-terminal) motifs and upon DNA damage is recruited to stalled replication forks, where it participates in a DNA damage checkpoint. Here we demonstrated an interaction between TopBP1 and E2F1. The interaction depended on the amino terminus of E2F1 and the sixth BRCT domain of TopBP1. It was specific to E2F1 and was not observed in E2F2, E2F3, or E2F4. This interaction was induced by DNA damage and phosphorylation of E2F1 by ATM. Through this interaction, TopBP1 repressed multiple activities of E2F1, including transcriptional activity, induction of S-phase entry, and apoptosis. Furthermore, TopBP1 relocalized E2F1 from diffuse nuclear distribution to discrete punctate nuclear foci, where E2F1 colocalized with TopBP1 and BRCA1. Thus, the specific interaction between TopBP1 and E2F1 during DNA damage inhibits the known E2F1 activities but recruits E2F1 to a BRCA1-containing repair complex, suggesting a direct role of E2F1 in DNA damage checkpoint/repair at stalled replication forks.

* Corresponding author. Mailing address: 520A Wallace Tumor Institute, 1530 3rd Ave. S, Birmingham, AL 35294-3300. Phone: (205) 934-3979. Fax: (205) 975-6911. E-mail: wclin{at}uab.edu.

Molecular and Cellular Biology, May 2003, p. 3287-3304, Vol. 23, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.9.3287-3304.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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